Abstract Chikungunya virus (CHIKV) is an emerging mosquito-transmitted alphavirus that causes an abrupt onset of fever with severe joint and muscle pain. In a significant number of patients chronic and debilitating arthritis can persists for months to years. CHIKV pathogenesis reflects an interplay between events controlling viral replication and the host inflammatory immune response. Key mediators of the host response to viral infection are type I interferons (IFNs), which collectively is comprised of 13 IFN-alpha (?) proteins and single IFN-beta (?), kappa (?), epsilon (?), and omega (?) proteins. The type I IFN response is known to control CHIKV infection, as mice lacking the type I IFN receptor (IFNAR) die soon after infection. However, the role of individual IFN subtypes is poorly understood. In preliminary data, we have found that IFN-?-/- and IRF7-/- (a surrogate for IFN-?) are more susceptible to CHIKV induced disease, whereas IFN-?-/- mice are resistant, providing evidence for functional differences between the IFN subtypes in vivo. In this proposal, we will define the mechanistic basis for how different type I IFN subtypes modulate CHIKV pathogenesis by exploring their ability to control viral replication and spread, function as immunomodulatory proteins, or temper the host response. In Aim 1 we will define the role that IFN-? plays during acute and chronic CHIKV infection by exploring its ability to limit viral replication and dissemination and determining whether IFN-? regulates the cell tropism of viral persistence. In Aim 2 we will determine the function of IFN-? during acute and chronic disease and evaluate its impact on modulating the cellular and adaptive immune response during acute and chronic infection. In Aim 3 we will investigate the novel actions of IFN-? by evaluating its impact on CHIKV pathogenesis in vivo and defining functional differences in signaling through IFNAR between IFN-?, IFN-?, and IFN-?. Overall, our studies will provide new insight into the effects of type I IFN immunity on CHIKV induced disease, which may promote the development of novel therapeutic strategies.